1. Field of the Invention
The decrease or reduction of toxicity, and the inhibition of ulcerogenesis and bleeding in the stomach, due to the ingestion of a pharmaceutically effective concentration or dosage of aspirin.
2. Description of the Prior Art
The extensive use of aspirin (acetyl salicylic acid) in medicine as an analgesic and as an anti-inflammatory agent or antipyretic is well known. Aspirin is used not only to treat various medical conditions, such as the alleviation of pain due to rheumatic and arthritic diseases, but is also used for temporary relief of minor aches and pains, colds misery, common or nervous tension headache, fever, etc. It has recently been established that, on a statistical basis, aspirin when regularly ingested is very effective in preventing strokes and heart attacks, especially in middle-aged men, evidently because of its mildly anti-coagulant properties, which tend to inhibit or prevent blood clots and improve circulation.
Aspirin is outstanding with respect to its low cost, safety, reliability, and almost universal effectiveness, and therefore is the medicine of choice for a number of conditions. Aspirin has also been suggested for usage as a growth stimulant in animal feeds, e.g. for stimulating the growth of ruminants, e.g. cattle, poultry, and swine, see U.S. Pat. No. 3,147,120.
Pharmaceutical compositions and the like containing aspirin as a component or ingredient have been suggested in U.S. Pat. Nos. 3,039,927; 4,113,856; 3,312,593; 3,928,588; 3,937,801; 4,153,691; 4,228,161; and 4,228,162.
Basically, and from a clinical viewpoint, the prognosis for aspirin therapy in most human subjects is good, especially if relatively low dosages of the aspirin are indicated. However, in some instances, and especially when the ingestion of a pharmaceutically effective high dosage or concentration of aspirin is prescribed, e.g. to alleviate the pain and suffering due to rheumatoid arthritis, the indicated aspirin therapy causes stomach ulceration, ischemia, or at least bleeding in the upper gastro-intestinal tract following oral administration. In most cases, such bleeding is so slight as to be harmless, but it can be a major problem in some patients, especially those who regularly take high doses, for example those who suffer from rheumatoid disease.
Thus aspirin, which exhibits a unique combination of effects on anti-inflammatory, antipyretic, and analgesic treatments, is perhaps the most popular and effective non-prescription analgesic drug. However, it has been cautioned that aspirin ingestion can cause severe gastro-intestinal bleeding in users and particularly in patients with gastro-intestinal lesions (P. R. Holt, Proc. Soc. Exp. Biol. Med., 102, 517 (1959); P. H. N. Wood, S. E. A. Harvey, and A. Dixon, Brit. Med. J., 1,669 (1962); M. I. Grossman, K. K. Matsumote, and R. J. Lichter, Gastro-enterology, 40, 383 (1961)). Although the mechanism by which the blood is lost is still unclear, studies (J. R. Leonards and G. Levy, J. Pharm. Sci., 58. 1277 (1969); and A. Weiss, E. R. Pitman, and E. C. Graham, Amer. J. Med., 31,266 (1961)), have shown that aspirin, when given orally in a liquid form or when given intravenously, produces no occult bleeding. On the other hand, aspirin tablet are found to cause gastric bleeding particularly when tablets disintegrate slowly and remain in the stomach as large tablet fragments. These results suggest that the gastric irritation by aspirin may be greatly reduced by reducing the particle size of the drug. The reduction of the drug particle size in the gastro-intestinal fluid may be best achieved by using a liquid dosage form. Hence, many attempts have been made to formulate a stable aspirin solution to reduce the undesirable side effect (H. R. Mehta and F. G. Drommond; J. Amer. Phar. Assoc. Pract. Ed., 15, 103 (1954); H. W. Tomski and L. S. Waller, Pharm. J., 144, 53 (1940); M. Farges, U.S. Pat. No. 3,316,150, Feb. 26, 1964; L. A. Luzzi, D. W. Whitworth, and H. W. Jun., J. Pharm. Sci., 62, 1184 (1973); and T. W. Schwarz, N. G. Suhvemar, and R. G. Renaldi, J. Amer. Pharm. Assoc. Pract. Ed., 19, 40 (1958)).
Thus, acute and chronic aspirin poisoning are important health and safety problems; there is therefore a need to develop antidotes having either preventive or therapeutic actions. Excessive aspirin ingestion may even cause death, or at least may cause ulcerogenesis or significant morbidity, manifested by reduced body weight gain, severe stomach distention, marked thinning of the forestomach, and severe blanching of the stomach wall, together with multiple severe gastric ulceration. In summary, in aspirin poisoning, like in stress ulceration induced by trauma, the stomach tissue has an abnormal coloration. Usually the stomach has a pinkish complexion due to blood contained in the capillaries that course the tissue. In the stressed or aspirin poisoned rat, the stomach looks dead white, due to the fact that during stress and aspirin poisoning the small blood vessels to the stomach are narrowed, thereby preventing blood flow to the cells of the stomach. As a consequence of this deprivation, stomach cells are prevented from getting adequate nutrients and oxygen that they normally get from blood. A secondary consequence is that nutrient and energy-deprived cells cannot prevent certain thermal or diffusion processes (acid) from occurring; furthermore, blood-starved tissues cannot synthesize components such as mucus that help maintain stomach cells in an environment that would, otherwise, digest them away. Another aspect of aspirin toxicity is the G.I. distension that occurs due to inhibited smooth muscle activity.
The use of various compounds, particularly salicylic acid derivatives, to combat the gastrointestinal ulceration associated with use of various anti-inflammatory drugs, is known. See, for example, (1) Hanchar et al, "Antiulcer Effect of Aspirin," Gastroenterology, Vol. 72, No. 5, Part 2 (1977), which reports the protective effect of aspirin, sodium salicylate, and aminopyrine when used with indomethacin; (2) British Pat. No. 1,483,165, which describes anti-flammatory compositions having decreased gastrointestinal side-effects comprising indomethacin or other anti-inflammatory agents together with salicylic acid or an alkali metal salicylate; (3) U.S. Pat. No. 4,016,268 which describes the use of bismuth subsalicylate co-administered with anti-inflammatory drugs to combat gastric ulceration associated with such drugs; (4) Robert and Asano, Prostaglandins, Vol. 14, No. 2, pp. 333-338 (1977), which describes the use of 16, 16-dimethyl PGE.sub.2 to prevent intestional lesions from indomethacin in experimental animals; (5) Japanese Patent Publication No. 5 3062 839 which discloses the use of mepirizole with non-steroidal anti-inflammatory agents to reduce ulcer formation caused by the latter; (6) Rainsford, Agents and Actions, Vol. 7, 516, pp. 573-577 (1977), which describes that while the mixture of indomethacin and probenecid is effective in reducing the gastric damage by indomethacin, the effect of aspirin and indomethacin is almost additive; (7) Goburdhum et al, J. Pharm. Methods., Vol. 1, pp. 109-114 (1978), which discloses that copper salicylate is more effective than sodium salicylate in achieving inhibition of the ulcerogenic effects of indomethacin; (8) U.S. Pat. No. 4,066,756, which discloses the use of sodium cromoglycate to inhibit the gastrointestinal irritation caused by indomethacin; and (9) Scrip, Oct. 14, 1973, p. 24, which discloses the use of parsalamide or rimazolium methylsulfate to reduce the ulcerogenic potential of indomethacin. However, unlike the majority of co-administered agents described in the prior art, particularly sodium salicylate and aspirin, the phenyl benzoic acid compounds are, surprisingly, many times more effective on a molar basis. Gastric ulceration in the rat has also been shown to be inhibited by salicylic acid or aspirin alone. See Pauls et al., Science, Jan. 2, 1948. Also pertinent are U.S. Pat. Nos. 2,283,817 and 4,292,298.